Acetoxymethyl acetamides and acetamidoacetamides and their preparation



3,534,031 Patented Oct. 13, 1970 ACETOXYMETHYL ACETAMIDES AND ACETA- MIDOACETAMIDES AND THEIR PREPARATION Stanley C. Bell, Penn Valley, Ronald J. McCaully, Mal- In the above series of reactions, the starting material is prepared by reacting anthranilic acid with chloracetyl chloride under known conditions, forming the expected chloroacetamide. The chlorine is then displaced with iodine, also under known conditions, to form the cor- 5 z i a i g gg gg g gfi f g 12 8; 52:35 3 2: respond ng iodoaceta-mlde shown as Compound IV. York, NX a corporation of Delaware The lsolated iodoacetamide s now reacted as (1) to No Drawing. Original application May 17, 1965, Ser. No. form an hydroxyammo acetamide (Compound V). This 456,533, now Patent No. 3,382,243, dated May 7, 1968. is carried out under carefully controlled reaction condi- Divided and this pP h 1967,5613 10 tions utilizing hydroxylamine, preferably as the hydro- 677,029 chloride or sulfuric acid salt, in an alcoholic solvent, pref- Ilii- (307 103/50; (307d 87/16 erably ethanol. The reaction media must have sufiicient CL 260-444 Clam basicity to yield free hydroxylamine and, therefore, enough base is added to give a stoichiometric excess of hydroxylamine. A pH from about neutrality to pH 9 will ABSTRACT OF DISCLOSURE I permit the reaction to proceed satisfactorily. A reaction A Process is disclosed in which an temperature from about 50 C. to 100 C., preferably -Y y y y 10We1' fatty acid amide is from about 70 C. to 80 C. has been found effective. P p y a reaction of an acid anhydride With a silb- The hydroxyaminoacetyl anthranilic acid is treated (Restituted aminoacetyl anthranilic acid. The reaction product actign 2) with a lower fatty acid anhydride, represented by is then treated with a compound possessing an active hy- (R CO) O i hi h R represents a lo r alkyl, prefdmgen a d a nucleophilic rou i.e., an amine, whereby erably methyl, under relatively mild conditions at about there iS formed a 2 carbamyl-acetanilide in which one 50 C, to 100 C, but preferable steam bath temperature nucleophilic group attaches to the methylene radical of the t f th b o i an N [(4 -4-H 3,1 b acetyl group and another 10 the Carbonyl g p of the oxazine 2 yl)acyloxymethyl] lower fatty acid amide, acetanilide. The compounds of the invention are central represented as Compound VIII, nervous system depressants, resulting in a generally e- The novel benzoxazine is then reacted with a compound laxing or sedative efiect. having an active hydrogen and a nucleophilic group as previously mentioned, which is represented as BH, the symbol B standing for a nucleophilic group such as an This application is a division of application Seli amino, a substituted amino, a morpholino, a lactam anion, flied y 1965, Which issued 011 y a sulfonamide anion, a substituted oxy or a substituted 1968 as US. Pat. 3,382,243. mercapto group. Thus, the nucleophilic reactant repre- This invention relates to novel substituted 2-acylamino sented as BH, is intended to cover ammonia; a mono. or acetamides, the intermediates for preparing m, and di-substituted amine, the substituent or substituents beparticularly the process for the manufacture and the use ing lower alkyl or aralkyl radicals; or morpholine thereof. The final Reaction 3 is carried out by reacting the acylh Process of the invention involves the P oxyacylarnino compound with a solution of the nucletl'eating'ail -i y g g or Y ophilic reactant, the desired reaction taking place at a acetyl anthranillc acid with a lower fatty acid anhydnde, 40 temperature within to C and preferably within for example anhfdnde that 5 an E T' the range of 20 to 80 C. Solvents useful in the reaction 1 )acetoxyme Y1] .acetaml T 6 may be the lower aliphatic alcohols, the lower alkyl ethers, atter 1s treated with a compound possessing at least one th 1 th th 1 hi h th reactive hydrogen atom combined with a nucleophilic 16 y e loxane oro er.1nert so Vents n W c e g p whereby the latter suprisingly causes ring rupture reactants are soluble, The reaction should take place under to form a 2-carbamylacetanilide by attaching as a sub- P condltlons, Y be reeilled y the erstituent to flua alpha carbon of the acfityl nucleus, and lStlCS of the nucleophilic reagent itself. Where the latter also attaches to the 2-carbonyl group on the benzene ring. 18 Weekly basic of 1S essehtiaiiy unfeactlve as a ase, as o method f r preparing h l. id d in the case of a lower alkanol, it is necessary to add a intermediates may be illustrated in the following specific 0 str y basic material, for p sodium hydroxide to sequence of reaction steps: cause the reaction to proceed in the desired direction. An

0 Nu-t i-onzi NHzOH NHCOCH NHOH (1) 01 o 0 OH 01 o 0 0H IV V l (R c o)20 (2) o o N NH-doHNHd-R H BH O-GHNHC-R T i) o a (a) 01 o OB 01 T II o I VHI amount of. base in excess of the stoichiometric amount is desirable.

The bicyclic Compound VIII may be made by another route which is illustrated specifically as follows:

VII

In the latter reaction sequence, where R has the meaning previously indicated, Compound VII- may first be prepared by reacting hydroxyaminoacetic acid with a selected lower fatty acid anhydride for the initial acylation reaction, after which one adds thionyl chloride. The minimum amount of anhydride necessary for complete reaction is used and the reaction is carried out at a temperature ranging from about 20 to 80 C. The temperature of reaction has been found to be critical and a temperature of about 60 to 70 C. will result in optimum yields. In place of the acid anhydride, one may use an acyl halide. Also, in place of thionyl chloride, which is preferred, one may use phosphorus pentachloride, or bromide.

The amination reaction with the halogenated anthranilic acid, identified as Reaction 4, is carried out at approximately room temperature, or, if necessary, at a temperature up to the refluxing temperature of the reaction mixture. This reaction replaces the reactive chlorine atom with the selected group of the anthranilic acid to form the desired acetamide represented as Compound IX.

In Reaction 5 the use of an acid anhydride or its equivalent also causes ring closure with the elimination of the acyloxy group and the attachment of an acyloxy group acting as a nucleophile to the methylene carbon. The reaction is carried out essentially as in the case of Reaction 2 preferably heating Compound IX with the acid anhydride on a steam bath, which results in the aforesaid benzoxazine, represented as Compound VIII.

The novel acetamides obtained in the final reactions with the nucleophilic compound, represented by Formula I, are pharmacologically active and deemed useful as central nervous system depressants, resulting in a generally relaxing or sedative effect. This was demonstrated by tests with mammals (mice) carried out by acceptable pharmacological procedures. In such procedures, standard graduated doses are used, normally up to 400 mg/kg. In this present case clearly observable decreased motor activity was noted in the neighborhood of about 100 mg./ kg. when the test compound was injected parenterally (IP).

The above mentioned final compounds may be characterized as generally white solids having relatively high melting points and crystallizable out of ethyl alcohol. They are substantially water-insoluble but soluble in the common polar solvents. When acid-addition salts can be formed, the latter are then Water-soluble to a material degree. The structural configuration of thecompounds was determined by the reactants used and confirmed by known measurement procedures including infra-red analysis and determination of the nuclear magnetic resonance spectrum.

The following examples illustrate the various features of the invention in greater detail. Temperatures as given are to be understood as being in degrees centigrade.

EXAMPLE 1 2-iodoacetamido-5-chlorobenzoic acid, M.P. 186-488 is prepared from 2-chloroacetamido-S-chlorobenzoic acid and a molar excess of sodium iodide in 200 ml. of acetone, refluxed for 3 hours, cooled and diluted with Water. The resultant precipitate was recrystallized from ethanol.

Analysis.Calcd. for C H CIINO (percent): N, 4.12; Cl, 10.44; I, 37.38. Found: (percent) N, 4.38; Cl, 10.40; I, 37.4.

EXAMPLE 2 2-chloroacetamido-5-chlorobenzoic acid, was prepared from 40 g. of 5-chloroanthranilic acid and 34 g. of chloroacetylchloride and the product, M.P. 214-217", was recrystallized from a water-alcohol mixture.

Analysis.Calcd. for C H Cl NO (percent) C, 43.56; H, 2.84; N, 5.64; Cl, 28.58. Found (percent): C, 44.02; H, 3.08; N, 5.59; Cl, 28.40.

EXAMPLE 3 5-chloro-N-(hydroxyaminoacetyl) anthranilic acid. To a solution of 136 g. of 2-iodoacetamido-5-chlorobenzoic acid in 800 ml. of ethanol, warmed to 75, was added a solution of 88 g. of hydroxylamine hydrochloride in 400 cc. of 4 N sodium hydroxide solution. The solution Was heated at for 10 min., chilled, and diluted with 1 l. of water to obtain the title product.

Analysis.-Calcd. for C H ClN O (percent): C, 44.3; H, 3.7; Cl, 14.5. Found (percent): C, 44.58; H, 3.78; Cl, 14.35.

EXAMPLE 4 N ([acetyl(acetoxy)amino] acetyl)-5-chloroanthranilic acid-A mixture of 2.0 g. of hydroxyaminoacetic acid was heated in 30 ml. of acetic anhydride with stirring for 20 min. at 60. The excess acetic anhydride was removed in vacuo and the residue dissolved in 20 ml. of methylene chloride and 6 ml. of thionyl chloride and refluxed for 5 min. The solvent was removed in vacuo and the residue was dissolved in 30 ml. of methylene chloride and added to 7 g. of 5-chloro-anthranilic acid in 60 ml. of 1,2-dimethoxyethane. The insoluble hydrochloride salt of the starting amine was filtered from the reaction mixture. The filtrate was concentrated to dryness and the residue recrystallized from ethanol giving the product, M.P. 182-183".

Analysis.-Calcd. for C H Cl'N O (percent): C, 47.50; H, 3.98; N, 8.52; Cl, 10.78. Found (percent): C, 47.72; H, 4.13; N, 8.37; Cl, 10.7.

EXAMPLE 5 N- ([acetyl(acetoxy)amino]acetyl) anthranilic acid, methyl ester, M.P. 94-96, is prepared from methyl anthranilate, hydroxyaminoacetic acid and acetic anhydride according to the procedure of Example 4.

Analysis.Calcd. for C H N O (percent): C, 54.54; H, 5.23; N, 9.09. Found (percent): C, 54.69; H, 5.18; N, 8.96.

EXAMPLE 6 N-[(6-chloro-4-oxo-4H 3,1 benzoxazin-Z-yDacetoxy methyl]acetamide.A solution of 3.6 g. of 5'-chloro-2- hydroxyaminoacetylanthranilic acid and 50 ml. of acetic anhydride was heated for 1 hour on the steam bath and partially concentrated. White crystals, 2.1 g. M.P. 208- 210 dec., were obtained on cooling.

Analysis.-Calcd. for C13H11C1N205 (percent): C, 50.25; H, 3.56; N, 9.02; CI, 11.41. Found (percent): C, 50.32; H, 3.52; N, 8.85; CI, 11.40.

EXAMPLE 7 2 acetamido 4' chloro-2-(methylamino)-2-methylcarbamoylacetanilide, M.P. 186189. A mixture of N[ (6- chloro-4-oxo-4H 3,1 benzoxazine-2-yl)acetoxymethyl] acetamide in ethanol was added dropwise to a solution of methylamine reactant in absolute ethanol. The solution was heated to 70 C. for one hour. The solvent and excess reactant were removed and the residue was crystallized from ethanol-water.

Analysis.Calcd. for C13H17C1N403 (percent): C, 49.91; H, 5.49; N, 17.91; Cl, 11.34. Found: (percent): C, 49.76; H, 5.08; N, 18.34; Cl. 11.5.

The invention claimed is:

1. The process comprising reacting 5-chloro-N-(hydroxyarninoacetyl) anthranilic acid with acetic anhydride at about steam bath temperature and forming the compound N-[ (6-chloro-4-oxo-4H-3,l-benzoxazin 2 yl)acetoxymethyl] acetamide.

2. The process of claim 1, wherein N-( [acetyl(acetoxy) amino] acetyl)-5-chloroanthranilic acid is reacted with acetic anhydride.

3. A compound having the formula:

\CCHNHCR3 References Cited UNITED STATES PATENTS 9/ 1963 Mofiett 260- 244 3 ,249,605 5/ 1966 Mofiett 260244 3,255,189 6/ 1966 Mofiett 260244 20 NATALIE TROUSOF, Primary Examiner US. Cl. X.R. 

